Project Summary This proposal looks to characterize biochemical differences between persons exposed and unexposed to manganese (Mn), by using metabolomics analysis methods. Mn is a known neurotoxicant that causes ?manganism?, a neurologic disorder that overlaps clinically with Parkinson's disease (PD). Given its known health effects and ubiquitous nature in the environment and many occupational micro-environments, identification of a valid and reproducible biomarker of Mn exposure or disease has been of interest to the environmental health and neurological research communities. Existing Mn biomarker studies have not reached consensus on a valid and reproducible biomarker of Mn exposure or disease when looking for elemental Mn in common biological specimens (blood, plasma, urine, hair), which is why metabolomics methods are being explored. Metabolomics is the study of the small molecules in biological systems (<1000 Daltons), often important in metabolic function and signaling or representing a fingerprint of a specific cellular process. Global metabolomics methods apply mass spectrometry in an untargeted approach to detect the small molecules found in a biological sample, often identifying tens of thousands of unique ions found in each sample. These metabolomics profiles can be compared between groups defined by different environments in order to identify specific ions associated with a feature such as exposure. This proposal has two main objectives. The first is to explore the metabolomics profiles in whole blood, plasma, and urine, collected from Mn-exposed and Mn- unexposed shipyard workers, on whom a well-characterized exposure history has been collected. The second is to use mass spectrometry and nuclear magnetic resonance methods to identify (by chemical name or empirical formula) those metabolites that are found to be associated with exposure, determine the biological pathway those metabolites are in, and use this information to determine how this pathway is involved in the Mn exposure-disease relationship. This proposed work will directly help promote the NIEHS mission, by discovering how Mn in the environment affects people at the biochemical level, which in turn could be used to promote healthier lifestyles for those with high exposure to Mn. This work will be done in concert with a training plan that will include coursework in analysis of big data (such as metabolomics data), environmental exposure modeling and assessment, and the use of biological data in health-based studies. In addition to coursework, the fellowship will support one-on-one mentoring with experts in metabolomics analysis methods and ion identification techniques, and participation in relevant seminars such as the NIEHS Exposure Sciences and the Exposome Webinar, and University of Washington seminars on Environmental Health and Data Science topics.